WO2022108381A1 - Composition pour la prévention ou le traitement d'une maladie neuro-inflammatoire comprenant de la didanosine - Google Patents

Composition pour la prévention ou le traitement d'une maladie neuro-inflammatoire comprenant de la didanosine Download PDF

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WO2022108381A1
WO2022108381A1 PCT/KR2021/017068 KR2021017068W WO2022108381A1 WO 2022108381 A1 WO2022108381 A1 WO 2022108381A1 KR 2021017068 W KR2021017068 W KR 2021017068W WO 2022108381 A1 WO2022108381 A1 WO 2022108381A1
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disease
didanosine
group
composition
lps
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PCT/KR2021/017068
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English (en)
Korean (ko)
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유성운
남혜리
이영환
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주식회사 오에이티씨
재단법인대구경북과학기술원
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Priority to JP2023530257A priority Critical patent/JP2023550749A/ja
Priority to EP21895148.1A priority patent/EP4289431A4/fr
Publication of WO2022108381A1 publication Critical patent/WO2022108381A1/fr
Priority to US18/047,392 priority patent/US11918599B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to a composition for preventing or treating neuroinflammatory diseases, and more particularly, to a composition for preventing or treating neuroinflammatory diseases, including didanosine or a pharmaceutically acceptable salt thereof.
  • the central nervous system consists of neurons and glial cells.
  • Glia cells account for about 90% of the total brain cells, and by volume account for about 50% of the total brain cells.
  • Glia cells can be further classified into three types: astrocytes, microglia, and oligodendrocytes.
  • microglia are a kind of differentiated macrophages, and are widely distributed in the brain. Microglia not only act as phagocytes that engulf tissue debris and dead cells, but also play a role in the brain's biodefense activities.
  • neuroinflammation is a kind of immune response of the nervous system, and is closely related to many neurodegenerative diseases including Alzheimer's, Parkinson's, and multiple sclerosis, and is currently considered a typical characteristic of neurodegenerative diseases.
  • Neuroinflammatory responses include activation of innate immune cells (microglia), release of inflammatory mediators such as nitric oxide (NO), cytokines and chemokines, and macrophage infiltration, which leads to neuronal cell death.
  • Inflammatory activation of microglia and astrocytes is thought to be a pathological marker and an important mechanism in the progression of neurodegenerative diseases. Since strict regulation of microglia activity is essential for maintaining brain homeostasis and preventing infections and inflammatory diseases, it is necessary to discover substances to alleviate neuroinflammation by modulating the activity of microglia.
  • didanosine is an FDA-approved nucleoside reverse transcriptase inhibitor used for the treatment of HIV/AIDS. It acts as a viral DNA chain terminator by inhibiting binding of the 5' to 3' phosphodiester linkage in the missing viral DNA. Didanosine can easily cross the blood brain barrier, so it can easily affect the brain. However, the effect of using didanosine to suppress neuroinflammation or act on the brain is unknown, and research on this is required.
  • an object of the present invention is to provide a composition for preventing, improving or treating neuroinflammatory diseases, including didanosine or a pharmaceutically acceptable salt thereof.
  • a further embodiment of the present invention relates to a method for preventing or treating a neuroinflammatory disease in a subject, comprising administering to a subject in need thereof a pharmaceutical composition comprising didanosine or a pharmaceutically acceptable salt thereof. .
  • a further embodiment of the present invention relates to didanosine or a pharmaceutically acceptable salt thereof, which is used for the prevention or treatment of a neuroinflammatory disease in a subject.
  • the composition may promote the degradation of amyloid beta.
  • the composition can restore memory by suppressing neuroinflammation.
  • An example of the present invention relates to a pharmaceutical composition for preventing or treating a neuroinflammatory disease comprising didanosine or a pharmaceutically acceptable salt thereof.
  • Another embodiment of the present invention relates to a composition for promoting amyloid beta degradation of microglia, comprising didanosine or a pharmaceutically acceptable salt thereof.
  • Another embodiment of the present invention relates to an anti-inflammatory composition for inflammation of the nervous system, comprising didanosine or a pharmaceutically acceptable salt thereof.
  • Another embodiment of the present invention relates to a composition for improving memory, comprising didanosine or a pharmaceutically acceptable salt thereof.
  • Another embodiment of the present invention relates to a method for preventing or treating a neuroinflammatory disease comprising administering to a subject a pharmaceutical composition comprising didanosine or a pharmaceutically acceptable salt thereof.
  • Another embodiment of the present invention relates to the use of a pharmaceutical composition comprising didanosine or a pharmaceutically acceptable salt thereof for the prevention or treatment of neuroinflammatory diseases.
  • Another embodiment of the present invention relates to the use of didanosine or a pharmaceutically acceptable salt thereof for producing a pharmaceutical composition for preventing or treating neuroinflammatory diseases.
  • Another embodiment of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising didanosine or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of neuroinflammatory diseases.
  • An example of the present invention relates to a pharmaceutical composition for preventing or treating a neuroinflammatory disease comprising didanosine or a pharmaceutically acceptable salt thereof.
  • “Didanosine” of the present invention is composed of the formula C 10 H 12 N 4 and 9-[(2R,5S)-5-(hydroxymethyl)oxolan-2-yl]-1H-purin according to IUPAC nomenclature It is named -6-one and refers to a compound having the structure of the following [Formula 1], and the active ingredient of the pharmaceutical composition for preventing, improving or treating neuroinflammatory diseases according to an embodiment of the present invention is didanosine, its It may be at least one selected from the group consisting of derivatives, metabolites, and pharmaceutically acceptable salts.
  • Didanosine represented by [Formula 1] may be used in the form of a salt.
  • acid addition salts formed with various pharmaceutically or food-acceptable organic or inorganic acids may be used.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates, and alkandioates. It can be obtained from non-toxic organic acids such as acids, aromatic acids, aliphatic and aromatic sulfonic acids.
  • non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, iodide, fluoride.
  • the acid addition salt according to the present invention is prepared by a conventional method, for example, by dissolving the compound of [Formula 1] in an excess acid aqueous solution, and dissolving the salt in a water-miscible organic solvent such as methanol, ethanol, acetone or It can be prepared by precipitation using acetonitrile. It can also be prepared by evaporating the solvent or excess acid from the mixture and drying the mixture, or by suction filtration of the precipitated salt.
  • a water-miscible organic solvent such as methanol, ethanol, acetone or It can be prepared by precipitation using acetonitrile. It can also be prepared by evaporating the solvent or excess acid from the mixture and drying the mixture, or by suction filtration of the precipitated salt.
  • didanosine represented by [Formula 1] can make a pharmaceutically or food-acceptable metal salt by using a base.
  • the alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. At this time, it is suitable for agrochemicals to prepare lithium, sodium, potassium or calcium salt as the metal salt.
  • the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
  • the term “neuroinflammatory disease” may include all diseases caused by inflammation of the nervous system.
  • the disease is multiple sclerosis, neuroblastoma, stroke, dementia, Alzheimer's disease, cognitive impairment, memory impairment, attention disorder, Parkinson's disease, Lou Gehrig's disease, Huntington's disease, Creutzfeldt-Jakob disease, post-traumatic stress disorder, depression, psychiatric It may be at least one selected from the group consisting of schizophrenia, neuropathic pain, and amyotrophic lateral sclerosis, but is not limited thereto.
  • the Alzheimer's disease may include, for example, sporadic Alzheimer's disease (SAD) or familial Alzheimer's disease (FAD). It is known that the main cause of familial Alzheimer's dementia is the PSEN gene, which expresses the transmembrane protein presenilin and the catalytic site of gamma-secretase.
  • SAD sporadic Alzheimer's disease
  • FAD familial Alzheimer's disease
  • the disease may be hereditary dementia or familial Alzheimer's disease (FAD). More specifically, the disease may be Alzheimer's disease or Alzheimer's-related dementia having one or more genetic mutations selected from the group consisting of Amyloid Precursor Protein (APP), Presenilin 1 (PSEN1), and Presenilin 2 (PSEN2).
  • the Presenilin 2 gene mutation may include one or more selected from the group consisting of A85V, N141Y, M174I, G212V, A237V, M239I and M239V in addition to PSEN2 N141I.
  • the disease may be cognitive impairment, memory loss, Alzheimer's disease or related symptoms caused by neuroinflammation, and may occur or worsen with aging, genetic mutation, head trauma, depression or complications caused by high blood pressure, etc. .
  • the neuroinflammation may be caused by one or more selected from the group consisting of genetic mutation, infection, brain trauma, and alcoholism.
  • the genetic mutation may be one or more genetic mutations selected from the group consisting of Amyloid Precursor Protein (APP), Presenilin 1 (Psen1), and Presenilin 2 (Psen2).
  • APP Amyloid Precursor Protein
  • Presenilin 1 Presenilin 1
  • Presenilin 2 Presenilin 2
  • Alzheimer's disease refers to dementia induced by artificially generating a neuroinflammatory response, and unlike the aging-induced dementia model, dementia can be expressed within a short period of time.
  • Alzheimerer by inducing neuroinflammation refers to dementia induced by artificially generating a neuroinflammatory response.
  • the subject and/or disease according to the present invention has one or more genetic mutations selected from the group consisting of Amyloid Precursor Protein (APP), Presenilin 1 (Psen1), and Psenilin 2 compared to a normal subject or normal disease. may be to have APP, Presenilin 1 (Psen1), and Psenilin 2 compared to a normal subject or normal disease. may be to have APP, Presenilin 1 (Psen1), and Psenilin 2 compared to a normal subject or normal disease. may be to have
  • composition according to an embodiment of the present invention may inhibit the expression of inflammatory cytokines in the central nervous system.
  • the inflammatory cytokine may be a neuroinflammatory cytokine.
  • the term “inflammatory cytokine” refers to a cytokine involved in an inflammatory response caused by bacterial or viral infection, tissue damage, etc.
  • the composition comprising didanosine or a salt thereof of the present invention is the inflammatory cytokine It may inhibit the expression of, and the inflammatory cytokine suppressed by the present invention may preferably be IL-6, but is not limited thereto.
  • inflammatory cytokines may be increased in neuroinflammatory diseases, and neuroinflammatory diseases such as Alzheimer's may be treated and improved by inhibiting inflammatory cytokines such as IL-6. Therefore, didanosine or a salt thereof according to the present invention suppresses the expression of inflammatory cytokines by restoring the damage of transcriptional activation factors, and thus can be usefully used in the treatment of neuroinflammatory diseases including Alzheimer's.
  • the composition comprising didanosine or a salt thereof as an active ingredient inhibits the expression of neuroinflammatory cytokines that cause neuroinflammation in microglia to prevent, improve or treat Alzheimer's through the anti-inflammatory effect of an animal model The effect was confirmed.
  • the secretion of IL-6 was significantly reduced in primary microglia of an animal model of Alzheimer's (see Example 6), and it was confirmed that there was almost no cytotoxicity. (see Example 5).
  • the composition according to an embodiment of the present invention may inhibit the expression of neuroinflammatory cytokines in microglia.
  • the microglia may have one or more genetic mutations selected from the group consisting of Amyloid Precursor Protein (APP), Presenilin 1 (PSEN1), and Presenilin 2 (PSEN2).
  • APP Amyloid Precursor Protein
  • PSEN1 Presenilin 1
  • PSEN2 Presenilin 2
  • the composition according to an embodiment of the present invention may be a composition for improving memory.
  • the present inventors studied a substance that can treat neuroinflammatory diseases by regulating the expression of inflammatory cytokines that cause an inflammatory response in microglia.
  • the present invention was completed by confirming that the anti-inflammatory effect appeared through the suppression of the expression of the inflammatory cytokine IL-6, and promotes the degradation of amyloid beta.
  • didanosine improved cognitive function in 5XFAD mice, which is another Alzheimer's disease model.
  • PSEN2 gene refers to a gene encoding a PSEN2 polypeptide.
  • the PSEN2 gene is the NCBI reference sequence.
  • the human PSEN2 gene is located at NC_000001.11 (226870594..226903829), and the mouse PSEN2 gene is located at NC_000067.7, including these sequences as well as known orthologs.
  • PSEN2 polypeptide is the NCBI reference sequence, the human PSEN2 protein is located at NP_000438.2, the mouse PSEN2 protein is located at NP_001122077, and includes these sequences as well as known orthologs.
  • A85V, N141I, N141Y, M174I, G212V, A237V, M239I, or M239V are known, and may include one or more of these mutations.
  • another embodiment of the present invention relates to an anti-inflammatory composition for neuroinflammation, comprising didanosine or a pharmaceutically acceptable salt thereof.
  • composition for improving memory comprising didanosine or a pharmaceutically acceptable salt thereof.
  • the composition according to the present invention may be usefully used as a pharmaceutical composition or a health functional food composition for improving or treating neuroinflammatory diseases, including Alzheimer's.
  • Another embodiment of the present invention relates to a composition for promoting amyloid beta degradation of microglia, comprising didanosine or a pharmaceutically acceptable salt thereof.
  • another embodiment of the present invention relates to the use of a pharmaceutical composition comprising didanosine or a pharmaceutically acceptable salt thereof to promote amyloid beta degradation in microglia.
  • another embodiment of the present invention relates to a pharmaceutical composition for use in promoting amyloid beta degradation in microglia, including didanosine or a pharmaceutically acceptable salt thereof.
  • the microglia may have reduced amyloid beta degradation due to neuroinflammation.
  • the microglia may have one or more genetic mutations selected from the group consisting of Amyloid Precursor Protein (APP), Presenilin 1 (PSEN1), and Presenilin 2 (PSEN2).
  • APP Amyloid Precursor Protein
  • PSEN1 Presenilin 1
  • PSEN2 Presenilin 2
  • the microglia may be microglia having a Presenilin 2 gene mutation, specifically, Psen2 N141I KI/+ microglia.
  • composition according to an embodiment of the present invention may be to restore the ability to degrade amyloid beta of microglia.
  • Another embodiment of the present invention relates to a food composition for preventing or improving neuroinflammatory diseases, including didanosine or a pharmaceutically acceptable salt thereof.
  • the food may be a health functional food.
  • the didanosine, the neuroinflammatory disease, etc. are the same as described above.
  • composition according to the present invention when in the form of a health functional food composition, it can be manufactured as a food with high medical and medical effects processed to efficiently exhibit bioregulatory functions in addition to food for specific health purposes and nutritional supply, and the food is Accordingly, it can be mixed as functional food, health food, and health supplement, and can be prepared in various forms such as tablets, capsules, powders, granules, liquids, pills, etc. to obtain useful effects.
  • the health functional food of the present invention may include additional ingredients that are commonly used in food compositions to improve odor, taste, vision, and the like.
  • vitamins A, C, D, E, B1, B2, B6, B12, niacin, biotin, folate, pantothenic acid, and the like may be included.
  • it may include minerals such as zinc (Zn), iron (Fe), calcium (Ca), chromium (Cr), magnesium (Mg), manganese (Mn), copper (Cu).
  • it may include amino acids such as lysine, tryptophan, cysteine, and valine.
  • preservatives potassium sorbate, sodium benzoate, salicylic acid, sodium dihydroacetate, etc.
  • disinfectants bleaching powder and high bleaching powder, sodium hypochlorite, etc.
  • antioxidants butylhydroxyanisole (BHA), butylhydroxytoluene (BHT) ), etc.
  • colorant tar pigment, etc.
  • color developer color developer
  • bleach sodium sulfite
  • seasoning MSG sodium glutamate, etc.
  • sweetener dulcin, cyclimate, saccharin, sodium, etc.
  • Food additives such as flavorings (vanillin, lactones, etc.), expanding agents (alum, D-potassium hydrogen tartrate, etc.), strengthening agents, emulsifiers, thickeners (flavors), film agents, gum base agents, foam inhibitors, solvents, and improving agents can be added.
  • the additive may be selected according to the type of food and used in
  • the health functional food of the present invention When used as a food additive, it may be added as it is or used together with other foods or food ingredients, and may be appropriately used according to a conventional method.
  • the content of didanosine is not particularly limited, and may be variously changed depending on the condition of the subject to be administered, the type of specific disease, the degree of progression, and the like. If necessary, it may also be included in the total content of the food.
  • Another embodiment of the present invention relates to a method of treating a neuroinflammatory disease comprising administering the pharmaceutical composition to a subject.
  • the pharmaceutical composition, the neuroinflammatory disease, etc. are the same as described above.
  • the “individual” may be a mammal such as a rat, livestock, mouse, or human, and specifically may be a dog, a racehorse, a human, etc. in need of treatment for a neuroinflammatory disease, for example, Alzheimer's disease, preferably a human. have.
  • the pharmaceutical composition of the present invention may be administered orally or parenterally (eg, intravenously, subcutaneously, intraperitoneally or locally applied) according to a desired method, and the dosage may vary depending on the subject's condition and body weight, disease Although it varies depending on the degree, drug form, administration route and time, it may be appropriately selected by those skilled in the art.
  • the pharmaceutical composition of the present invention may be administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level depends on the type of disease, severity, drug activity, and drug. It can be determined according to factors including sensitivity, administration time, administration route and excretion rate, duration of treatment, concomitant drugs, and other factors well known in the medical field.
  • the pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be determined by a person skilled in the art.
  • the effective amount of the pharmaceutical composition of the present invention may vary depending on the subject's age, sex, condition, weight, absorption of the active ingredient into the body, inactivation rate and excretion rate, disease type, and drugs used in combination, in general 0.001 to 4 mg per kg of body weight can be administered daily or every other day, or divided into 1 to 3 times a day. However, since it may increase or decrease depending on the route of administration, sex, weight, age, etc., the dosage is not intended to limit the scope of the present invention in any way.
  • the composition according to an embodiment of the present invention is less than 1 times, 0.9 times or less, 0.8 times or less, 0.7 times or less, 0.6 times or less, 0.5 times or less, 0.4 times or less, the effective amount of didanosine administered as an HIV therapeutic agent, 0.3 times or less, 0.2 times or less, 0.1 times or less, 0.09 times or less, 0.08 times or less, 0.07 times or less, 0.06 times or less, 0.05 times or less, 0.04 times or less, 0.03 times or less, 0.02 times or less, or 0.01 times or less it may be At this time, even if the lower limit of the dosage is not specified, a person skilled in the art will be able to clearly practice the present invention for the prevention or treatment of neuroinflammatory diseases.
  • It may be 0.0001 times or more, 0.0005 times or more, 0.001 times or more, 0.005 times or more, 0.01 times or more, 0.05 times or more, or 0.1 times or more of the didanosine effective amount, but is not limited thereto.
  • the composition according to an embodiment of the present invention is 0.001 to 4 mg/kg, 0.001 to 3 mg/kg, 0.001 to 2.5 mg/kg, 0.001 to 2 mg/kg, 0.001 to 1.5 mg/kg, 0.001 to 1 mg/kg, 0.001 to 0.9 mg/kg, 0.001 to 0.8 mg/kg, 0.001 to 0.7 mg/kg, 0.001 to 0.6 mg/kg, 0.001 to 0.5 mg/kg, 0.001 to 0.45 mg/kg, 0.001 to 0.4 mg/kg, 0.005 to 4 mg/kg, 0.005 to 3 mg/kg, 0.005 to 2.5 mg/kg, 0.005 to 2 mg/kg, 0.005 to 1.5 mg/kg, 0.005 to 1 mg/kg, 0.005 to 0.9 mg /kg, 0.005 to 0.8 mg/kg, 0.005 to 0.7 mg/kg, 0.005 to 0.6 mg/kg, 0.005 to 0.5 mg/kg, 0.005 to 0.45 mg/kg, 0.001 to
  • prevention refers to any action that suppresses or delays the onset of a neuroinflammatory disease by administration of the pharmaceutical composition according to the present invention.
  • improvement means any action that reduces the symptom level of neuroinflammatory disease by administration of the composition according to the present invention
  • treatment refers to any action in which symptoms for neuroinflammatory disease are improved or beneficially changed by administration of the pharmaceutical composition according to the present invention.
  • treatment includes the reduction or alleviation of at least one symptom associated with or caused by the condition, disorder or disease being treated.
  • a treated subject may exhibit partial or total remission of symptoms (eg, Alzheimer's disease or an associated condition) or symptoms may remain static after treatment in accordance with the present invention.
  • treatment is intended to include prevention, therapy and cure.
  • composition according to the present invention when in the form of a pharmaceutical composition, it may contain a pharmaceutically effective amount of didanosine alone or one or more pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carriers are those commonly used in formulation, and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose. , polyvinyl pyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil.
  • a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. may be additionally included in addition to the above components.
  • Another embodiment of the present invention relates to the preventive or therapeutic use of the pharmaceutical composition for neuroinflammatory diseases.
  • the pharmaceutical composition, the neuroinflammatory disease, etc. are the same as described above.
  • Another embodiment of the present invention relates to the use of the pharmaceutical composition to produce a pharmaceutical composition for the prevention or treatment of neuroinflammatory diseases.
  • the pharmaceutical composition, the neuroinflammatory disease, etc. are the same as described above.
  • Another embodiment of the present invention relates to the pharmaceutical composition for use in the prevention or treatment of neuroinflammatory diseases.
  • the pharmaceutical composition, the neuroinflammatory disease, etc. are the same as described above.
  • composition according to an embodiment of the present invention can inhibit the expression of neuroinflammatory cytokines, so it is effective for neuroinflammatory diseases, and it has been confirmed that it improves the cognitive function of Alzheimer's mice. It is expected that it can be used.
  • composition according to an embodiment of the present invention suppresses the expression of neuroinflammatory cytokines, promotes the decomposition of amyloid beta, and can improve cognitive function in an animal model of Alzheimer's disease. It is expected to be useful in the development of quasi-drug materials and related industries.
  • FIG. 1 is for the construction of a Psen2 N141I mutant Alzheimer's disease mouse model according to an embodiment of the present invention
  • FIG. 1a is a schematic diagram for N141I target insertion
  • FIG. 1b is normal (wild type)
  • KI / + is normal (wild type)
  • FIG. 2 confirms that the Psen2 N141I mutant Alzheimer's disease mouse model according to an embodiment of the present invention causes an excessive inflammatory response compared to normal (wild-type) mice.
  • the blood levels of IL-6 in animals induced by neuroinflammation are shown.
  • IL-6 was overexpressed in Psen2-mutant Alzheimer's mice at all LSP concentrations, and the expression difference between normal mice and Alzheimer's models gradually widened at low concentrations.
  • 2B shows the production of TNF- ⁇ by intraperitoneal injection of LPS, and at all LPS concentrations, TNF- ⁇ shows the same blood concentration between normal mice and Psen2 N141I mutant Alzheimer’s mice.
  • Figure 2c shows the changes in the blood concentration of inflammatory cytokines IL-6, CXCL1, CCL2, CCL5.
  • LPS 0.35 ⁇ g/kg
  • Figure 3a shows Iba-1 (microglia marker antibody) staining images in the hippocampus of normal mice and Psen2 N141I mutant Alzheimer's mice
  • Figure 3b is a 3D filament image of Iba-1 signals using IMARIS software
  • Figure 3c shows dendrite length and number of branches data through FilamentTracker analysis of IMARIS software.
  • FIG. 4 is the result of confirming that the Psen2 N141I mutant Alzheimer's mouse model exhibits memory deterioration by intraperitoneal injection of a low concentration of LPS. It has been confirmed Figure 4b shows that there is no difference in the motility of mice in the Y-maze analysis.
  • FIG. 4c is a schematic diagram of the T-maze assay method, and FIG. 4d confirms that the Psen2 N141I mutant mice induced by neuroinflammation through the T-maze analysis showed a significantly lower success rate and deterioration of memory.
  • IL-6 an inflammatory factor
  • WT wild-type
  • KI/+ Alzheimer's animal model Psen2 N141I KI/+ mice
  • FIG. 7 is a view confirming that didanosine restores the decreased amyloid beta degradation ability of microglia derived from wild-type (WT) and Alzheimer's animal model Psen2 N141I KI/+ mice (KI/+).
  • FIG. 8 is a view confirming that the amount of IL-6 hypersecreted by neuroinflammation is significantly reduced in wild-type (WT) and Alzheimer's animal model Psen2 N141I KI/+ mice (KI/+).
  • 9a is a view confirming that didanosine administration does not affect motility.
  • 9B is a view confirming that didanosine has an effect of recovering a decrease in memory ability.
  • 11a is a view confirming that didanosine administration does not affect motility in wild-type mice and animal models of 5XFAD disease.
  • Figure 11b is a view confirming that didanosine has the effect of restoring the memory loss in the 5XFAD disease animal model.
  • Psen2 N141I/+ mice were used to more accurately reproduce human neuroinflammatory diseases, such as Alzheimer's disease, and to maintain endogenous expression levels.
  • Psen2 N141I/+ mice were generated using homologous recombination.
  • a Psen2 N141I knock-in (KI) animal model in which N (arginine) at amino acid 141 of the presenilin 2 gene is substituted with I (isoleucine) as one of familial Alzheimer's mutations was prepared.
  • the targeting vector contains the I141 mutation in the exon 4 region and the Neo r -loxp sequence.
  • the homology region of the targeting vector was inserted into Psen2 of the wild-type (WT) allele.
  • Psen2 N141I/N141I ;loxp-Neo r - loxp mice were crossed with Cre mice using the Cre-loxp system to generate a Psen2 N141I mutant knock-in mouse model.
  • Psen2 N141I means that the normal Psen2 gene of the animal model is substituted to express the same mutation as the dementia mutation reported in humans, and more specifically, amino acid 141 of the mouse Presenilin 2 gene is from N to I means replaced with
  • the polynucleotide of SEQ ID NO: 1 is used as the Psen2 N141I gene, and the wild-type Psen2 gene is shown in SEQ ID NO: 2.
  • KI mice carrying the Psen2 N141I allele ( Psen2 N141I/+ and Psen2 N141I/N141I ) were generated.
  • the substitution of AAC and ATC in Asparagine (N) consisting of the AAC sequence is a KI/+ model having both Asparagine (N) and Isoleucine (I), and KI/KI having I141 substituted with ATC all
  • the model was confirmed by genomic sequencing of DNA extracted from the tail of the mouse.
  • This Example was performed to confirm that the Psen2 N141I mutant Alzheimer's disease mouse model caused excessive inflammatory response compared to normal (wild-type) mice.
  • mice 8-week-old wild-type and Psen2 N141I/+ mice were intraperitoneally (ip) injected with LPS at 18:00 (Zeitgeber time). 11:00, 07:00, turn off at 19:00) 20 hours later, the inflammatory response was monitored at 14:00 the next day.
  • LPS was obtained from Escherichia coli 0111:B4 strain, and acts as a ligand of Toll-like receptor 4 to induce an immune response in cells. 100 ⁇ l of LPS diluted in phosphate-buffered saline (PBS) according to the concentration was injected intraperitoneally into the mouse.
  • PBS phosphate-buffered saline
  • neuroinflammation was induced by intraperitoneal injection of 1.4, 3.6, 4.0, 25, and 5,000 ⁇ g/kg LPS into the Psen2 N141I mutant Alzheimer’s disease mouse model obtained in Example 1.
  • group 1 is a wild-type mouse not injected with LPS (WT(LPS(-))
  • group 2 is a wild-type mouse injected with various LPS (WT(LPS(+)))
  • group 3 is a wild-type mouse that is not injected with LPS.
  • Alzheimer's disease mouse model KI/+(LPS(-))
  • group 4 was prepared with various LPS-injected Alzheimer's disease mouse models (KI/+(LPS(+))). 5 to 8 mice were used in each group.
  • Table 1 shows the mean values (mean ⁇ SEM) of blood concentrations of L-6 and TNF- ⁇ in each group.
  • IL-6 was overexpressed by intraperitoneal injection of various concentrations of LPS, and the expression difference between wild-type mice and Alzheimer's disease mouse models gradually widened at low concentrations.
  • TNF- ⁇ exhibited identical blood levels between wild-type mice and the Alzheimer's disease mouse model.
  • both IL-6 and TNF-a secretion were very low and the same.
  • mice of groups 1 to 4 were prepared in the same manner as in Example 2-1, except that in groups 2 and 4, instead of LPS treatment at various concentrations, a low concentration of LPS that did not cause an inflammatory reaction in wild-type mice ( 0.35 ⁇ g/kg) was used.
  • Serum was extracted from the mouse model in the same way, and the amount of each protein was measured by ELISA according to the kit manufacturer's instructions.
  • the blood concentrations of IL-6, CXCL1, CCL2, and CCL5, which are inflammatory cytokines, analyzed in the sera of mice of groups 1 to 4 are shown in Table 2 below.
  • Table 2 shows the changes (mean ⁇ SEM) of plasma concentrations of inflammatory cytokines IL-6, CXCL1, CCL2, and CCL5.
  • group 2 when wild-type mice were injected with a low concentration of LPS (0.35 ⁇ g/kg) that did not cause an inflammatory response, it was confirmed that, unlike TNF- ⁇ , inflammatory cytokines were significantly increased only in Psen2 Alzheimer's disease mice in group 4.
  • the lowest LPS dose (0.35 ⁇ g/kg body weight) did not cause inflammation in wild-type mice, but the plasma concentrations of inflammatory cytokines (IL-6, CXCL1, CCL2 and CCL5) were significantly higher in Psen2 Alzheimer's disease mice. shows a significant increase.
  • Example 3 Confirmation of exacerbation of inflammation in an animal model of neuroinflammation using microglia morphology analysis
  • microglia It is characterized that the morphology of microglia is closely related to its function, and activation of microglia is associated with shape change. To determine whether increased production of inflammatory cytokines is reflected in the morphology of microglia. For this purpose, through immunohistochemical analysis, the shape of microglia in the hippocampus of wild-type and Psen2-mutant Alzheimer's disease mice was investigated using an antibody against Iba-1, a microglia-specific marker.
  • mice were anesthetized by injecting a mixture of zoletyl (Virbac, 50 mg/kg) and rumpun (Bayer, 10 mg/kg). Thereafter, the mice were perfused with PBS and fixed by perfusion with 4% paraformaldehyde (PFA). Brains were collected and fixed with 4% PFA for 16 hours, then transferred to 30% sucrose until they settled to the bottom of the tube, and then stored using a frozen solution. A brain sample sliced to a thickness of 50 ⁇ m in the coronal direction was subjected to antigen retrieval at 95°C and then IBA-1 antibody (1:250) in PBS containing 3% bovine serum albumin at 4°C for 24 hours. After treatment, the secondary antibody was treated at room temperature for 2 hours. Images were taken using an LSM 7 and LSM 700 confocal laser scanning microscope.
  • microglia in the hippocampus of group 1 wild-type mice had small cell bodies with highly divergent processes, and consistent with the absence of cytokine release induction, low-dose LPS was administered to group 2 wild-type mice. While the morphology of hippocampal microglia was not altered, hippocampal microglia from group 3 Psen2-mutant Alzheimer's disease mice showed shorter, round-shaped enlarged somatic cells even in the absence of LPS injection. It was confirmed that group 4 was further increased by LPS injection.
  • Fig. 3b histological confocal images of microglia of the mouse hippocampus of groups 1 to 4 were reconstructed in 3D form and various morphological parameters were measured using IMARIS software. Specifically, images were obtained by summing the entire Z-axis of randomly selected fields with a confocal microscope, and then 3D imaging was performed using IMARIS software (v9.2.1, bitplane AG).
  • mice of Groups 1 to 4 prepared in Example 2-2 were prepared 20 hours after LPS injection.
  • the LPS concentration injected into groups 2 and 4 was obtained using a low concentration of LPS (0.35 ⁇ g/kg) that did not cause an inflammatory response in wild-type mice.
  • the Y-maze is used to evaluate spatial working memory. Performed on white plastic arms of a Y-shaped maze, rats were placed in their arms and allowed to freely explore the arms for 5 min. Experiments were recorded with EthoVision software (Noldus). The number of entries and the number of triads were analyzed to calculate the alternation by dividing the number of three consecutive entries by the number of possible triads ⁇ 100 (total arm entries minus 2).
  • Table 4 above shows the average value (mean ⁇ SEM) of the Y-maze shift ratio and the number of arm entries in each group.
  • the arm shift in Y-maze was proportional to inflammatory cytokine secretion in group 1 wild-type mice (13 mice) and LPS-injected wild-type mice group 2 (13 mice).
  • the total number of arm entries was the same in all groups, so it was confirmed that they represent normal motor function.
  • mice of Groups 1 to 4 prepared in Example 2-2 were prepared in Example 2-2.
  • the LPS concentration injected into groups 2 and 4 was obtained using a low concentration of LPS (0.35 ⁇ g/kg) that did not cause an inflammatory response in wild-type mice.
  • T-maze was used to evaluate spatial learning and memory for rewards.
  • the T-shaped maze was performed on white plastic arms, and the mice were acclimatized to the maze and food reward for 5 minutes before the experiment, and in the subsequent trial, both arms were blocked with one arm and the other side was rewarded.
  • the mouse arrives at the open arm to check the reward, and in the next trial, the previously closed arm is opened, the mouse is started again, and the reward can be checked if the newly opened arm is selected. If the mouse chooses the wrong arm it had previously visited, it will not be rewarded.
  • the number of trials in which the correct arm was visited over multiple trials is calculated as a percentage of the total trials.
  • Table 5 shows the average value (mean ⁇ SEM) of the success rate of the T-maze performance of each group.
  • group 1 wild-type mice (11 mice) and LPS-injected group 2 (11 mice) there was no difference in learning and memory abilities in proportion to inflammatory cytokine secretion.
  • group 3 Alzheimer's disease mice (10 mice) without LPS injection but it was significantly reduced in group 4 Alzheimer's disease mice group (10 mice) injected with LPS. .
  • LPS low dose LPS induces hyperactivity of immune response and induced memory deficit through overproduction of inflammatory cytokines including IL-6 in Psen2 N141I KI/+ Alzheimer's disease mice, whereas LPS at the same dose was confirmed to be harmless to wild-type mice.
  • mice brains were extracted from newborn wild-type mice 1 to 3 days old, then cells were isolated, and 10% heat-inactivated fetal bovine serum (HI-FBS, Hyclone) and 1 % penicillin-streptomycin (Hyclone) supplemented with Dulbecco's modified Eagle's medium (DMEM, Corning) was cultured.
  • Primary microglia were isolated on day 12 by tapping in vitro. The purity of primary microglia was estimated by immunostaining with anti-Iba-1 antibody, a microglia marker.
  • apoptosis rate was measured by treating microglia of wild-type (WT) mice with didanosine at a concentration of 1, 5, or 10uM.
  • Didanosine CCL-D1-000017-G06 was provided by the Korea Chemical Bank and used in the experiment.
  • the microglia prepared in Example 5-1 were seeded in a 96-well plate at a density of 5 x 10 4 .
  • the seeded cells were treated with didanosine at a concentration of 0, 1, 5 or 10 ⁇ M for 12 hours, and then co-stained with Hoechst 33342 (Invitrogen, H3570) and propidium iodide (PI; Sigma-Aldrich, P4170) to prevent apoptosis. measured. Images of stained cells were captured using a fluorescence microscope (Axiovert 40 CFL; Carl Zeiss) and Hoechst positive and PI positive cells were counted using NIH ImageJ software. Cell death rate (%) was calculated as (PI-positive [dead] cells / Hoechst-positive [total] cells) ⁇ 100.
  • Brains were isolated from the Psen2 N141I KI/+ mice prepared in Example 1 and the wild-type mice 1 to 3 days after birth. Primary microglia derived from wild-type and Psen2 N141I KI/+ mice were cultured according to Example 5-1.
  • the prepared microglia were pretreated with didanosine at a concentration of 0, 5 or 10 ⁇ M for 30 minutes, and LPS derived from Escherichia coli 0111:B4 (L4391) was further treated at a concentration of 1 ⁇ g/mL, and secreted into the culture medium after 12 hours
  • the amount of cytokine IL-6 produced was measured by ELISA.
  • An ELISA kit for mouse IL-6 was purchased from R&D system and used to measure cytokines in culture medium according to the manufacturer's instructions.
  • the groups treated with didanosine in the primary cultured microglia were classified as follows.
  • Brains were isolated from the Psen2 N141I KI/+ mice prepared in Example 1 and the wild-type mice 1 to 3 days after birth.
  • Primary microglia derived from wild-type and Psen2 N141I KI/+ mice were cultured according to Example 5-1. The prepared microglia were isolated and cultured, and seeded together with a cover glass in a 24-well plate.
  • FITC signal-bound amyloid beta 1-42 was prepared according to the following reference (Cho, M.-H. et al. “Autophagy in microglia degrades extracellular ⁇ -amyloid fibrils and regulates the NLRP3 inflammasome.” Autophagy 10 , 1761-1775 (2014)).
  • FITC-conjugated amyloid beta oligomers were fibrillized in media for 24 hours.
  • the prepared aggregated (fibrilized) amyloid beta 1-42 was directly treated in the culture medium of microglia at a concentration of 4 ⁇ M. After that, the aggregated amyloid beta was treated and washed after 2 hours to remove the amyloid beta remaining in the media without being fed.
  • the cells were immobilized and placed on a slide glass, and then the amount of aggregated amyloid beta remaining in the cells was measured to compare the degree of decomposition.
  • the amount of amyloid beta was measured using a confocal laser scanning microscope (LSM700) to capture the entire z-axis of cells in a randomly selected field at an interval of 2 ⁇ m, and the number of pixels of the FITC-labeled amyloid beta signal present in the cell was determined by ZEN ( Black edition; Carl Zeiss) was calculated through software and quantified by measuring the relative fluorescence intensity.
  • LPS at a concentration of 0.35 ⁇ g/kg did not induce an inflammatory response in wild-type mice, and thus did not increase the IL-6 cytokine blood concentration, corresponding to a very low concentration.
  • Psen2 N141I KI/+ mice neuroinflammation was induced, resulting in overproduction of IL-6.
  • didanosine at a concentration of 5 mg/kg corresponds to a concentration of 0.4 mg/kg (24 mg/60 kg) for humans, and is about 0.1 times lower than the 250 mg daily dose prescribed for HIV treatment.
  • didanosine restored the memory loss of Alzheimer's-induced Psen2 N141I KI model mice to that of wild-type mice.
  • the low concentration of LPS did not cause a decrease in memory and did not affect motility in the normal group, so the normal group administered with LPS was compared to the normal group not administered with LPS. There was no difference in memory and motility.
  • Brains were isolated from the Psen2 N141I KI/+ mice prepared in Example 1 and the wild-type mice 1 to 3 days after birth. Primary microglia derived from wild-type and Psen2 N141I KI/+ mice were cultured according to Example 5-1.
  • the prepared microglia were first treated with LPS at a concentration of 1 ⁇ g/mL, and then treated with didanosine at a concentration of 10 ⁇ M 1 hour later, and cytosine secreted into the culture medium 11 hours later.
  • the amount of Cain IL-6 was measured by ELISA.
  • An ELISA kit for mouse IL-6 was purchased from R&D system and used to measure cytokines in culture medium according to the manufacturer's instructions.
  • Each group treated with didanosine in the primary cultured microglia was divided as follows. 10 and Table 12, as a result of treatment with didanosine in Psen2 N141I KI/+ mouse-derived microglia induced by LPS neuroinflammation, the increased secretion of IL-6 was significantly reduced. . Therefore, the therapeutic effect of didanosine on neuroinflammation was confirmed.
  • APP and PSEN1 gene (APP; Swedish (K670N/M671L), Florida (I716V), and London (V717I) mutations and PSEN1; M146L and L286V as one of the animal models used for Alzheimer's disease research mutations) expressing the 5XFAD mouse model was used.
  • APP and PSEN1 mutant genes are expressed by the Thy1 (mature neuron-specific marker) promoter, and even hemizygous mice show severe amyloid pathology and behavioral deficits.
  • Thy1 mature neuron-specific marker
  • mice and wild-type mice were intraperitoneally injected with didanosine at a concentration of 0.5 mg/kg/day for a total of 4 weeks, 5 consecutive days per week.
  • Didanosine at a concentration of 0.5 mg/kg corresponds to a concentration of 0.04 mg/kg (2.4 mg/60 kg) for humans, and is about 0.01 times lower than the 250 mg daily dose prescribed for HIV treatment.
  • Example 12 Evaluation of neuroinflammation recovery using a 5xFAD mouse model
  • Example 11 After the end of the experiment, the hippocampal tissue of 5xFAD mice was isolated and the gene expression of IL-6 ( Il-6 ) was investigated. Specifically, Il-6 mRNA expression level was measured by qRT-PCR (Quantitative RT-PCR) method, RNA was isolated from the isolated hippocampal tissue, and cDNA was synthesized using ImProm-II Reverse Transcriptase kit (Promega). PCR primers were synthesized commercially (Cosmo Genetech). qRT-PCR was performed using Taq Polymerase (Invitrogen) specific for mouse cDNA and the primers shown in Table 15 below.
  • qRT-PCR Quantitative RT-PCR

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Abstract

La présente invention concerne une composition pour prévenir ou traiter une maladie neuro-inflammatoire, qui peut inhiber l'expression de cytokines neuro-inflammatoires, favoriser la dégradation de la bêta-amyloïde, et améliorer une fonction cognitive dans un modèle animal de la maladie d'Alzheimer. Plus particulièrement, la présente invention concerne une composition pour la prévention ou le traitement d'une maladie neuro-inflammatoire comprenant de la didanosine ou un sel pharmaceutiquement acceptable de celle-ci, et la composition peut être utilisée pour le développement de médicaments et de matières quasi-médicamenteuses.
PCT/KR2021/017068 2020-11-19 2021-11-19 Composition pour la prévention ou le traitement d'une maladie neuro-inflammatoire comprenant de la didanosine WO2022108381A1 (fr)

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